Certain tricyclic pyrido[3,2,1-ij]cinnoline-8-carboxylates, useful as antimicrobial agents

ABSTRACT

A compound represented by the following general formula: ##STR1## which is useful as an intermediate for production of a clinically excellent synthetic antibacterial, a salt thereof, and a process for producing the same. 
     In said formula, 
     R 1  is a hydrogen atom or a carboxyl-protecting group; 
     R 2  is a hydrogen atom or a lower alkyl group; 
     X 1  is a hydrogen atom or a halogen atom; 
     X 2  is a halogen atom; 
     X a   5  is a hydrogen atom or a halogen atom; 
     A is a methylene group; a group of &gt;CH--COOR 4 , etc., 
     in which R 4 , R 5  and R 6  each are a hydrogen atom or a carboxyl-protecting group; 
     B is a methylene group or a carbonyl group; 
     provided that both A and B must not be methylene groups at the same time.

TECHNICAL FIELD

The present invention relates to new tricyclic compounds. Moreconcretely, it relates to new tricyclic compounds or sales thereof whichare useful as intermediates for producing synthetic microbicidesexcellently suitable to clinical use, and also to a process forpreparing them.

Accordingly, one object of the present invention is to provide newtricyclic compounds or salts thereof which are useful as intermediatesfor producing synthetic microbicides excellently suitable to clinicaluse.

Another object of the present invention is to provide a new industrialprocess for preparing such tricyclic compounds or salts thereof, whichis excellent in point of the yield and purity of the products.

DISCLOSURE OF THE INVENTION

New tricyclic compounds of the present invention are compounds or saltsthereof which are represented by the following general formula: ##STR2##where R¹ is a hydrogen atom or a carboxyl-protecting group;

R² is a hydrogen atom or a lower alkyl group;

X¹ is a hydrogen atom or a halogen atom;

X² is a halogen atom;

X_(a) ⁵ is a hydrogen atom or a halogen atom;

A is a methylene group; a group of >CH--COOR⁴, or a group of: ##STR3##in which R⁴, R⁵ and R⁶ each are a hydrogen atom or a carboxyl-protectinggroup;

B is a methylene group or a carbonyl group;

provided that both A and B must not be methylene groups at the sametime.

In accordance with the present invention, tricyclic compounds (A) can beprepared by the process (1) or process (2) as illustrated in thefollowing schemes. ##STR4## or a salt thereof or a salt thereof wherein

R¹, R², R⁴, R⁵, R⁶, X¹ and X² are each as defined above,

R⁸ is an amino-protecting group,

X³ is a split-off group,

X⁵ is a hydrogen atom , a halogen atom, an amino group or a protectedamino group,

X_(b) ⁵ is a halogen atom, and

R_(a) ¹ is a carboxyl- protecting group.

The starting compounds (II), (III) and (IV) can be prepared, forexample, by the following processes each comprising a series of theillustrated steps. ##STR5## wherein R¹, R², R⁴, R⁵, R⁶, X¹, X², X³ andX⁵ are each as defined above,

R³ is an amino-protecting group,

R⁷ and R⁹ are each lower alkyl,

X⁴ is a split-off group,

R^(a) is a lower alkyl,

R^(b) is a hydrogen atom, or a lower alkyl,

X^(a) is a halogen atom.

Suitable salts of compounds (A) are both acid-addition salts thereof andbase-addition salts thereof. Acid-addition salts of compounds (A)include, for example, (a) salts thereof with mineral acids such ashydrochloric acid, sulfuric acid, etc.; (b) salts thereof with organiccarboxylic acids such as formic acid, citric acid, trichloroacetic acid,trifluoroacetic acid, etc.; and (c) salts thereof with sulfonic acidssuch as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, mesitylenesulfonic acid, naphthalenesulfonic acid, etc.Base-addition salts of compounds (A) include, for example, (a) saltsthereof with alkali metals such as sodium, potassium, etc.; (b) saltsthereof with alkaline earth metals such as calcium, magnesium, etc.; (c)ammonium salts thereof; and (d) salts thereof with nitrogen-containingorganic bases such as trimethylamine, triethylamine, tributylamine,pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, cyclohexylamine, procaine, dibenzylamine, 1-ephenamine,N,N'-dibenzylethylenediamine, etc.

In the above and subsequent description of this specification, suitableexamples of the various definitions are explained in detail as follows:

The term "lower" is intended to mean 1 to 6, preferably 1 to 4, carbonatom(s), when the substituent is a linear or branched group; and to mean3 to 7 carbon atoms, when it is a cyclic group.

The term "carboxyl-protecting group" indicates the ester residue of acarboxylate and is intended to mean anyone which may relatively easilybe cleaved to give the corresponding free carboxyl group. Specificexamples of the group include, for example, groups which may split offby treatment under mild conditions, for example, by hydrolysis orcatalytic reduction, such as a lower alkyl group (e.g., methyl, ethyl,n-propyl, tert-butyl, etc.), a lower alkenyl group (e.g., vinyl, allyl,etc.), an aralkyl group (e.g., benzyl, benzhydryl, etc.), an aryl group(e.g., phenyl, etc.), etc.; and groups which may easily split off, suchas a lower alkanoyloxy-lower alkyl group (e.g., acetoxymethyl,pivaloyloxymethyl, etc.), a lower alkoxycarbonyloxy-lower alkyl group(e.g., methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, etc.), alower alkoxymethyl group (e.g., methoxymethyl, etc.), a lactonyl group(e.g., phthalidyl, etc.), a boron group substituted by substituent(s)selected from a halogen atom, a lower alkanoyloxy group, a halo-(lower)alkanoyloxy group and an aroyloxy group (e.g., benzoyloxy, toluoyloxy,naphthoyloxy), such as difluoroboron etc., as well as a di-loweralkylamino-lower alkyl group (e.g., 1-dimethylaminoethyl, etc.), and a(5-methyl-2-oxol-4-yl)methyl group.

The term "lower alkyl" includes, for example, methyl, ethyl, isopropyl,tert-butyl, tert-pentyl, and the like.

The "split-off group" includes, for example, halogen atoms such asfluorine atom etc., which will be mentioned hereunder.

The "halogen" may include, chloro, bromo, fluoro and iodo.

Suitable "protecting groups" of the "protected amino group" include, forexample, an acyl group, such as a lower alkanoyl group (e.g., formyl,acetyl, propionyl, pivaloyl, hexanoyl, etc.), a mono- (or di-ortri-)halo(lower)alkanoyl group (e.g., chloroacetyl, bromoacetyl,dichloroacetyl, trifluoroacetyl, etc.), a lower alkoxycarbonyl group(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.), acarbamoyl group, an aroyl group (e.g., benzoyl, toluoyl, naphthoyl,etc.), an ar(lower)alkanoyl group (e.g., phenylacetyl, phenylpropionyl,etc.), an aryloxycarbonyl group (e.g., phenoxycarbonyl,naphthyloxycarbonyl, etc.), an aryloxy(lower)alkanoyl group (e.g.,phenoxyacetyl, phenoxypropionyl, etc.), an arylglyoxyloyl group (e.g.,phenylglyoxyloyl, naphthylglyoxyloyl, etc.), an optionally substitutedar (lower)alkoxycarbonyl group (e.g., benzoyloxycarbonyl,phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.); a substituted orunsubstituted ar(lower)alkylidene group (e.g., benzylidene,hydroxybenzylidene, etc.); and an ar(lower)alkyl group, such as amono-(or di- or tri-)phenyl(lower)alkyl group (e.g., benzyl, phenethyl,benzhydryl, trityl, etc.).

The "cyclo-lower alkylamino group" includes, for example, acyclopropylamino group, a cyclobutylamino group, etc.

The "mono- or di-lower alkylamino group" includes, for example, amethylamino group, an ethylamino group, a dimethylamino group, abenzylamino group, etc.

The "cyclic amino group optionally having substituent(s)" may be eithera saturated cyclic amino group or an unsaturated cyclic amino group andmay contain additional one or more hetero atoms such as nitrogen,oxygen, sulfur atoms and others and/or carbonyl carbon atoms in thering, and it may be mono-cyclic, bi-cyclic or tri-cyclic.

The cyclic amino group is preferably a saturated or unsaturated 4- to9-membered ring, including, for example, an azetidinyl group, apyrrolidinyl group, a piperidino group, a pyrrolinyl group, a pyrrolylgroup, an imidazolyl group, a piperazinyl group, a homopiperazinylgroup, a morpholino group, a thiomorpholino group, a2,5-diazabicyclo[2.2.1]heptan-2-yl group, a3,8-diazabicyclo[3.2.1]octan-8-yl group, a dihydroisoindolyl group, etc.Examples of substituents which may be into the cyclic amino group are alower alkyl group, a lower alkenyl group, a lower aralkyl group, an arylgroup, a hydroxyl group, a hydroxy-lower alkyl group, a substituted orunsubstituted amino group, a substituted or unsubstituted amino-loweralkyl group, a cyclic amino group as mentioned above, an alkoxy group,an alkoxy-lower alkyl group, a halogen atom, a halo-lower alkyl group,an acyloxy group, an acyloxy-lower alkyl group, an acyl group, acarboxyl group, a carboxy-lower alkyl group, an alkoxycarbonyl-loweralkyl group, a mercapto group, a lower alkylthio group, a cyano group, anitro group, etc.

The alkyl group includes, for example, a methyl group, an ethyl group,an n-propyl group, etc.; the lower alkenyl group includes, for example,a vinyl group, an allyl group, etc.; a lower aralkyl group includes, forexample, a benzyl group, a phenethyl group, etc.; the hydroxy-loweralkyl group includes, for example, a hydroxymethyl group, a hydroxyethylgroup, a hydroxypropyl group, etc.; the amino-lower alkyl groupincludes, for example, an aminomethyl group, a 1-aminoethyl group, a2-aminoethyl group, a 1-amino-1-methylethyl group, etc.; the alkoxygroup includes, for example, a methoxy group, an ethoxy group, ann-propoxy group, etc.; the alkoxy-lower alkyl group includes, forexample, a methoxymethyl group, an ethoxymethyl group, etc.; the halogenatom includes, for example, a fluorine atom, a chlorine atom, a bromineatom, etc.; the halo-lower alkyl group includes, for example, afluoromethyl group, a trifluoromethyl group, etc.; the acyloxy groupincludes, for example, an acetoxy group, a benzoyloxy group, etc.; theacyloxy-lower alkyl group includes, for example, an acetoxymethyl group,a benzoyloxymethyl group, etc.; the acyl group includes, for example,those mentioned above, etc.; the carboxy-lower alkyl group includes, forexample, a carboxymethyl group, a carboxyethyl group, etc.; thealkoxycarbonyl-lower alkyl group includes, for example, amethoxycarbonylmethyl group, a t-butoxycarbonylmethyl group, etc.; andthe lower alkylthio group includes, for example, a methylthio group, anethylthio group, etc.

Of those mentioned above, the substituents in the substituted aminogroup and the substituted amino-lower alkyl group include, for example,a lower alkyl group (e.g., methyl, ethyl, etc.), a lower cycloalkylgroup (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), a loweralkenyl group (e.g., vinyl, allyl, etc.), a lower aralkyl group (e.g.,benzyl, phenylethyl, etc.), an aryl group (e.g., phenyl, etc.), an acylgroup (e.g., those mentioned above, etc.), an amino acid residue orpeptide residue (e.g., Gly-, Leu-, Val-, Ala-, Phe-, Ala-Ala-, Gly-Val-,Gly-Gly-Val-, etc.), and a protected amino acid residue or peptideresidue in which the functional group(s) is/are protected withprotective group(s) which is/are ordinarily used in peptide chemistry,such as an acyl group, a lower aralkyl group, etc., and a cyclic aminogroup. The number of the substituents may be 1 to 3, and they may freelybe selected from same or different ones. The amino acid-protecting groupis preferably one which may split off from the compound and may besoluble in a body. Especially preferred is an alanyl group.

Where Y is a group of R¹⁰ --(CH₂)m--O-- and R⁷ is an optionallysubstituted amino group, nitrogen-containing saturated heterocyclicgroup or lower cycloalkyl group, the substituent(s) to be in the groupof R⁷ may be the same one(s) as that those to be in the above-mentionedcyclic amino group. The lower cycloalkyl group includes, for example, acyclopropyl group, a cyclobutyl group, etc.; and the nitrogen-containingsaturated heterocyclic group is preferably a 4- to 9-membered ring,which may be the same one as the saturated hetero ring as referred tofor the above-mentioned cyclic amino group. Especially preferred as thehetero ring is a 3-azetidinyl group, a 3-pyrrolidinyl group, etc. Thebond between the saturated heterocyclic group and --(CH2)m--O-- may beat any atom in the ring of the former.

The processes for preparing the object compound (A) of the presentinvention are explained in detail in the following.

PROCESS 1 Step 1-A

The compound (III) or a salt thereof can be prepared by reacting acompound (II) or a salt thereof and a conjugated double bond-havingcompound (IV) by Michel addition reaction.

Suitable salts of the compounds (II) and (III) can be referred to theones as exemplified for the compound (A).

The reaction is carried out in the presence of a base or a Lewis acid.Preferred base may include, for example, an alkali metal hydride such assodium hydride, potassium hydride, etc.; an alkaline earth metal hydridesuch as calcium hydride, etc.; an alkali metal alkoxide such aspotassium tert-butoxide, etc.; and potassium fluoride, etc. PreferredLewis acid may include, for example, a zinc halide such as zinc bromide,zinc chloride, etc.; a magnesium halide such as magnesium bromide,magnesium chloride, etc.; a titanium compound such as titaniumtetrachloride, tetraethoxy titanium, tetrapropoxy titanium, etc.; borontrifluoride, etc.

The reaction is usually carried out in a solvent such as water, analcohol [e.g., methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide,N-methylpyrrolidone, a mixture thereof or any other solvent which doesnot adversely influence the reaction.

As an auxiliary agent which may be used along with the solvent or Lewisacid, for example, mentioned are compounds having ether bond(s) formodifying the acidity of the Lewis acid, such as diethyl ether,1,2-epoxypropane, tetrahydrofuran, dioxane, etc.

The reaction temperature is nor critical and the reaction is usuallycarried out under heating.

Step 1-B

The compound (A-1) or a salt thereof can be prepared by subjecting thecompound (III) or a salt thereof to the ring-closing reaction.

Suitable salts of the compounds (A-1) can be referred to the ones asexemplified for the compound (A).

The ring-closing reaction is effected in the presence of a base. Assuitable examples of the base and solvent, those illustrated in the step1-A are referred to.

The reaction temperature is not critical and the reaction is usuallycarried out under heating.

Depending upon the reaction condition (for example, usingdimethylsulfoxide as the solvent), the ring-closing reaction of the step1-B is effected simultaneously with the Michel addition of the step 1-Aand the reaction progresses in one step as a whole.

Step 2

The compound (A-2) or a salt thereof can be prepared by subjecting thecompound (A-1) or a salt thereof to the solvolysis reaction.

Suitable salts of the compounds (A-2) can be referred to the ones asexemplified for the compound (A).

Preferred base is an inorganic base or organic base, including, forexample, an alkali metal such as sodium, potassium etc.; an alkalineearth metal such as magnesium, calcium, etc.; a hydroxide, carbonate orhydrogencarbonate of the metal; a trialkylamine such as trimethylamine,triethylamine, etc.; as well as picoline,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, etc.

Preferred acid may include, for example, an organic acid such as formicacid, acetic acid, glacial acetic acid, propionic acid, trichloroaceticacid, trifluoroacetic acid, etc.; and an inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride,hydrogen bromide, etc.

Removal to be effected by the use of a Lewis acid such as atrihaloacetic acid, for example, trichloroacetic acid, trifluoroaceticacid, etc., is preferably effected in the presence of a cation-capturingagent such as anisol, phenol, etc.

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, a mixturethereof or any other solvent which does not adversely influence thereaction. A liquid base or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Step 3

The compound (A-3) or a salt thereof can be prepared by subjecting thecompound (A-2) or a salt thereof to the decarboxylation reaction .

Suitable salts of the compounds (A-3) can be referred to the ones asexemplified for the compound (A).

The reaction is carried out under heating in an inert gas atmospheresuch as nitrogen, etc. or by an ordinary method such as reduction.

The reaction is usually carried out in a solvent such as water, analcohol [e.g.: methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, a mixturethereof or any other solvent which does not adversely influence thereaction.

The reaction temperature is not critical and the reaction is usuallycarried out under warming to heating.

Step 4-A

The compound (A-5) or a salt thereof can be prepared by reacting thecompound (A-4) or a salt thereof with the amine compound(V) or a saltthereof.

Suitable salts of the compounds (A-4) and (A-5) can be referred to theones as exemplified for the compound (A).

The reaction is generally effected by using an equivalent amount or asomewhat excess amount of the compound (V) or a salt thereof to thecompound (A-2) or a salt thereof, in the presence of sodium carbonate,calcium carbonate, sodium hydrogencarbonate, triethylamine, DBU, etc. Asthe case may be, an excess amount of the compound (V) may be used, whichhas an additional role of an acid acceptor in the reaction.

The reaction may be effected, in general, in any solvent which does nothave any bad influence on the reaction and which includes, for example,aromatic hydrocarbons such as benzene, toluene, xylene, etc.; etherssuch as tetrahydrofuran, dioxane, monoglyme, etc.; halogenatedhydrocarbons such as methylene chloride, chloroform, etc.; aprotonicpolar solvents such as dimethylformamide, dimethylsulfoxide, etc.; andacetonitrile, pyridine, etc.

The reaction temperature is not critical and the reaction is usuallycarried out under warming to heating.

Step 4-B

The compound (A-6) or a salt thereof can be prepared by subjecting thecompound (A-5) or a salt thereof to the elimination reaction of theamino-protecting group.

Suitable salts of the compounds (A-6) can be referred to the ones asexemplified for the compound (A).

To the reaction of removing the amino-protecting group, any ordinaryreaction condition for hydrolysis or catalytic reduction may be applied.Concretely, in the case of hydrolysis, the reaction is effected in asolvent, for example, water; an alcohol such as methanol, ethanol,isopropyl alcohol, etc.; a ketone such as acetone, methyl ethyl ketone,etc.; an ether such as dioxane, ethylene glycol, diethyl ether, etc.;acetic acid, etc., or in a mixed solvent of them, in the presence of abasic compound such as sodium hydroxide, potassium hydroxide, bariumhydroxide, potassium carbonate, etc.; a mineral acid such as sulfuricacid, hydrochloric acid, nitric acid, etc.; or an organic acid such asacetic acid or an aromatic sulfonic acid. The reaction is effectedgenerally at room temperature to about 200° C., preferably roomtemperature to about 120° C.

In the case of catalytic reduction, the reaction is effected in asolvent such as methanol, ethanol, propanol, acetic acid,tetrahydrofuran, dioxane, ethyl acetate, water, etc., or in a mixedsolvent of them, in the presence of a catalyst of palladium-carbon,palladium-black, platinum dioxide, etc., generally with stirring in ahydrogen stream of atomic pressure to 100 barometric pressures. Thereaction temperature is at room temperature to about 100° C., and thereaction is finished generally in 1 to 48 hours.

Step 5

The compound (A-8)or a salt can be prepared by subjecting the compound(A-7)or a salt to the elimination reaction of the carboxyl-protectinggroup.

Suitable salts of the compounds (A-7) and (A-8) can be referred to theones as exemplified for the compound (A).

To the reaction of removing the carboxyl-protecting group, any ordinaryreaction condition for hydrolysis or catalytic reduction may be applied.Concretely, those mentioned in the previous step 4-B are referred to.

PROCESS (2) Step 1

The compound (A-9) or a salt thereof can be prepared by subjecting thecompound (VI) or a salt thereof to the cyclization reaction.

Suitable salts of the compounds (A-9) can be referred to the ones asexemplified for the compound (A).

The cyclization reaction is effected by an ordinary method such asdehydrohalogenation.

The reaction is preferably effected in the presence of a base. Preferredbase may include, for example, an alkali metal hydride such as sodiumhydride, potassium hydride, etc.; an alkaline earth metal hydride suchas calcium hydride, etc.; an alkali metal alkoxide such as potassiumtert-butoxide, etc.; potassium fluoride, etc.

The reaction is preferably effected in the presence of a copper salt,such as cuprous iodide, cuprous or cupric chloride, etc.

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, a mixturethereof or any other solvent which does not adversely influence thereaction.

The reaction temperature is not critical and the reaction is usuallycarried out under heating.

Step 2

The compound (A-10) or a salt thereof can be prepared by subjecting thecompound (A-9) or a salt thereof to the elimination reaction.

Suitable salts of the compounds (A-10) can be referred to the ones asexemplified for the compound (A).

In the reaction of removing the esterified carboxyl group, both thedeesterification and the decarboxylation are conducted simultaneously orsuccessively.

The reaction is effected by an ordinary method such as solvolysis,reduction, etc.

The solvolysis is preferably effected in the presence of a base or anacid (including Lewis acids). Preferred base is an inorganic base or anorganic base, including, for example, an alkali metal such as sodium,potassium, etc.; an alkaline earth metal such as magnesium, calcium,etc.; a hydroxide, carbonate or hydrogencarbonate of the metal; atrialkylamine such as trimethylamine, triethylamine, etc.; as well aspicoline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.

Preferred acid may include, for example, an organic acid such as formicacid, acetic acid, glacial acetic acid, propionic acid, trichloroaceticacid, trifluoroacetic acid, etc.; and an inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride,hydrogen bromide, etc.

Removal to be effected by the use of a Lewis acid such as atrihaloacetic acid, for example, trichloroacetic acid, trifluoroaceticacid, etc., is preferably effected in the presence of a cation-capturingagent such as anisol, phenol, etc.

Reduction to be applied to the reaction includes chemical reduction andcatalytic reduction. Regarding the reducing agents to be used forreduction, any and every conventional ones may be used. For instance,the chemical reducing agent may include, for example, combination of ametal such as tin, lead, iron, etc.; or a metal compound such aschromium chloride, chromium acetate, etc.; and an organic or inorganicacid such as formic acid, acetic acid, propionic acid, trifluoroaceticacid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.;aluminium lithium hydride; sodium boron hydride; combination of sodiumboron hydride and trifluoroacetic acid or pyridine; combination ofsodium boron hydride and phosphoryl chloride; and borane-methylsulfidecomplex; and the catalyst for catalytic reduction may include, forexample, a platinum catalyst such as platinum sheet, platinum sponge,platinum black, colloidal platinum, platinum oxide, platinum wire, etc.;a palladium catalyst such as palladium sponge, palladium black,palladium oxide, palladium-carbon, colloidal palladium, palladium-bariumsulfate, palladium-barium carbonate, etc.; a nickel catalyst such asreduced nickel, oxidized nickel, Raney nickel, etc.; a cobalt catalystsuch as reduced cobalt, Raney cobalt, etc.; an iron catalyst such asreduced iron, Raney iron, etc.; and a copper catalyst such as reducedcopper, Raney copper, Ullmann copper, etc.

Where the group of R⁴ is an allyl group, the reaction may be effected inthe presence of an allyl group-capturing agent of capturing the allylgroup to be generated in the reaction system, the allyl group-capturingagent including, for example, a palladium compound such as palladiumacetate, tetrakis(triphenylphosphine) palladium(O), bis(dibenzylideneacetone) palladium(O),di[1,2-bis(diphenylphosphino)ethane] palladium(O), tetrakis(triphenylphosphite) palladium (0), etc.; an amine such as morpholine,N-methylaniline; an active methylene compound such as dimedone, benzoylacetate, 2-methoxy-3-oxo-valeric acid, etc.; a cyanohydrin compound suchas cyanated α-tetrahydropyranyloxybenzyl, etc.; a lower alkanoic acid ora salt thereof such as formic acid, acetic acid, ammonium formate,sodium acetate, etc.; and N-hydroxysuccinimide, etc. The reaction ismore preferably effected in the presence of triphenylphosphine, etc.

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, dioxane, N,N-dimethylformamide, ethylene glycoldimethyl ether, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Step 3

The compound (A-12) or a salt thereof can be prepared by subjecting thecompound (A-11) or a salt thereof to the elimination reaction of thecarboxyl-protecting group. Suitable salts of the compounds (A-11) and(A-12) can be referred to the ones as exemplified for the compound (A).

To the reaction of removing the carboxyl-protecting group, any ordinaryreaction condition for hydrolysis or catalytic reduction may be applied.Concretely, those mentioned in the step 4-B in the process 1 arereferred to.

Step 4-1

The compound (A-3) or a salt thereof can be prepared by reducing thecompound (A-10) or a salt thereof.

As the reduction to be applied to the reaction, the ordinary reductionmethod as mentioned in the previous step 2 may be referred to.

Therefore, the above-mentioned explanation may be referred to.

Step 4-2a

The compound (VII) or a salt thereof can be prepared by reducing thecompound (A-10) or a salt thereof.

Suitable salts of the compounds (VII) can be referred to the ones asexemplified for the compound (A).

The reaction is effected, for example, in the presence of a reducingagent, such as sodium boron hydride, combination of sodium boron hydrideand boron trifluoride-diethyl ether complex, etc.

The reaction is usually carried out in a solvent such as pyridine,tetrahydrofuran or any other solvent which does not adversely influencethe reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Step 4-2b

The compound (A-11) or a salt thereof can be prepared by subjecting thecompound (VII) or a salt thereof to the dehydrogenation reaction.

The reaction is effected, for example, in the presence of a catalystsuch as manganese dioxide, etc.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as ethyl acetate.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The compounds obtained by the above Process 1(step 1 to step 5) toProcess 2 (step 1 to step 4) can be isolated and purified by aconventional method such as extraction, pulverization, precipitation ,fractional crystallization, recrystallization, column chromatography, orthe like.

Not only the compounds (A) are useful as a microbicide by themselves butalso some of them are useful as intermediates for producing othermicrobicides of the same kind, which is described in Japanese PatentApplication No. 2-211190.

For the reagents and the reaction conditions, for example, the solventsand the reaction temperatures, for the production methods A, B and C forthe starting materials (II), (III) and (VI), for example, thepreparation examples mentioned below are referred to. For the startingsubstances (a) and (b) in the production methods A and B, for example,the description of Japanese Patent Application Laid-Open No. 59-212474and the preparation examples mentioned below are referred to.

The tricyclic compounds (A) or salts thereof may be converted tosynthetic microbicides (B) which are advantageous to clinical use, inaccordance with the preparation process mentioned below, which issimilar to the process described in Japanese Patent Application No.2-211190 or 3-80144. ##STR6## wherein R¹, R³, X¹, X² and X⁵ are each asdefined above;

Y is an amino group, a cyclo-lower alkylamino group, a mono- ordi-(lower)alkylamino group, an optionally substituted cyclic aminogroup, or a group of R10--(CH2)m--O--, in which R10 is a hydrogen atom,an optionally substituted amino group, an optionally substitutednitrogen-containing saturated heterocyclic group, or an optionallysubstituted lower cycloalkyl group, and m is an integer of 0 to 3; and

M is a hydrogen atom or an alkali metal atom.

The compound (B) is obtained by reacting the compound (A) and an aminecompound or a salt thereof or an alkali metal alcoholate of Y--M.

The salt of an amine to be used may be an acid-addition salt thereof.

The reaction is effected desirably in an inert reaction solvent such asacetonitrile, N,N-dimethylformamide, dimethylsulfoxide, sulforane orN-methylpyrrolidone or in a mixed solvent of them.

The reaction temperature is preferably 50° to 200° C., more preferably80° to 150° C.

The reaction is desirably effected, with neutralizing the hydrogenhalide to be generated during the reaction by the use of a base such astriethylamine, lutidine, 1,8-diazabicyclo[5.4.0]undeca-7-ene,1,5-diazabicyclo[4.3.0]nona-5-ene, an alkali metal carbonate, etc.Neutralization of the hydrogen halide to be generated may also beeffected by the use of an excess amount of the reactant alkali metalalcoholate or amine.

In the reaction, the product may often be obtained in the form of a saltthereof. If desired, the salt may be treated with an acid such as aceticacid, trifluoroacetic acid, hydrochloric acid, etc., or a base such assodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, etc., so that the product is converted into the correspondingfree form.

Next, the present invention will be explained by way of the followingpreparations and examples.

EXAMPLES Preparation 1

A mixture comprising ethyl 2,3,4,5,6-pentafluorobenzoylacetate (28.6 g),ethyl orthoformate (23.2 g) and acetic anhydride (32.3 g) was heatedunder reflux for 8 hours. The mixture was concentrated under reducedpressure, then dissolved in methylene chloride (100 ml). To the solutionwas added methylene chloride (30 ml) solution ofN-(tert-butoxycarbonyl)-N-methylhydrazine (14.6 g) at 0°˜10° C., stirredfor 2 hours, and the solvent was removed by distillation. The oilyproduct obtained was crystallized with n-hexane and filtered to obtainethyl2-(2,3,4,5,6-pentafluorobenzoyl)-3-(2-tert-butoxycarbonyl-2-methylhydrazino)acrylate(18.2 g).

To N,N-dimethylformamide (50 ml) solution of ethyl acrylate was addedpotassium carbonate (6.2 g) and heated at 70° C. for one hour. Themixture was poured into ice-cold water (200 ml), to give a solid. Thesolid was collected by filtration and dissolved in chloroform (200 ml),washed with water and dried over magnesium sulfate, and concentratedunder reduced pressure. The oily product obtained was crystallized withn-hexane to obtain ethyl1-(N-tert-butoxycarbonyl-N-methylamino)-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(13.7 g).

Preparation 2

Ethyl 1-(N-tert-butoxycarbonyl-N-methylamino)-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.2 g) was dissolved in ethylacetate (30 ml),. 4N hydrochloric acid-dioxane solution (40 ml) wasadded thereto with ice-cooling and stirred overnight at roomtemperature, and the solvent was removed by distillation. The residuewas dissolved in chloroform (100 ml), and 10% sodium carbonate aqueoussolution (50 ml) was added thereto and stirred for 30 minutes at roomtemperature. The organic layer was separated out and dried overmagnesium sulfate, and the solvent was removed by distillation. Thecrystals were dispersed in ether and filtered out to obtain ethyl1-methylamino-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.9 g).

Preparation 3

A solution of 1-tert-butoxycarbonyl-1-methylhydrazine(2.88 g) in ethanol(3 ml) was dropwise added to a solution of ethyl2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate(6.00 g) in ethanol (15ml) at 0°˜10° C.

The mixture was stirred at 0°˜10° C. for 30 minutes and at ambienttemperature for one hour. Diisopropyl ether (40 ml) was added to themixture to give a solid. The solid was collected by filtration and driedover phosphorus pentaoxide under reduced pressure to give ethyl2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-tert-butoxycarbonyl-2-methylhydrazino)acrylate(6.41 g).

mp: 123°-124° C. IR(Nujol): 3175, 1720, 1678 cm⁻¹ NMR(CDCl₃, δ):isomerA1.00(3H, t, J=7.1 Hz), 1.49(9H, s), 3.25(3H, s), 4.05 (2H, q, J=7.1 Hz),8.02(1H, d, J=11.6 Hz), 10.29(1H, d, J=11.6 Hz) isomer B 1.14(3H, t,J=7.1 Hz), 1.50(9H, s), 3.29(3H, s), 4.11(2H, q, J=7.1 Hz), 8.08(1H, d,J=11.2 Hz), 11.75(1H, d, J=11.2 Hz)

Preparation 4

A suspension of ethyl2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-tert-butoxycarbonyl-2-methylhydrazino)acrylate(10.50 g)and potassium carbonate (3.80 g)in dimethylformamide (31.5ml)was heated at 60°˜65° C. for one hour. The mixture was poured intoice-water (300 ml) to give a solid. The solid was filtered , dissolvedin dichloromethane (100 ml), dried over magnesium sulfate, andconcentrated under reduced pressure to give a residue. The residue wastriturated with n-hexane to give ethyl1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(9.25 g).

mp: 125°-126° C. IR(Nujol): 1732, 1720, 1695 cm⁻¹ NMR(CDCl₃, δ):1.3-1.7(12H), 3.43(3H, s), 4.39(2H, d, J=7.1 Hz),8.12(1H, ddd, J=2.1 Hz,7.8 Hz, 10.0 Hz), 8.37(1H, s)

Preparation 5

To 4N hydrochloric acid solution (46 ml) in ethyl acetate was addedethyl1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(9.20 g) under ice-cooling and the mixture was stirred at the samecondition for 2 hours. Diisopropyl ether (90 ml) was added to themixture to give a solid. The solid was collected by filtration, anddried over phosphorus pentaoxide under reduced pressure to give ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro -4-oxoquinoline-3-carboxylatehydrochloride(6.26 g).

mp: 137°-141° C. IR(Nujol): 1665 cm⁻¹ NMR(CDCl₃, δ): 1.41(3H, t, J=7.1Hz), 2.98(3H, z), 4.38(2H, q, J=7.1 Hz), 8.15 (1H, ddd, J=2.2 Hz), 8.0Hz, 10.1 Hz), 8.66(1H, s)

Preparation 6

To a solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate hydrochloride(5.91 g)in dichloromethane(100 ml) was added a saturated aqueous sodium hydrogencarbonate solution(50 ml) and the mixture was stirred at ambient temperature for 30minutes. The organic layer was washed with brine (50 ml), dried overmagnesium sulfate, and concentrated under reduced pressure to give asolid. The solid was recrystallized from dichloromethane-n-hexane togive ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(5.14 g).

mp: 149°-150° C. IR(Nujol): 1723 cm⁻¹ NMR(CDCl₃, δ): 1.39(3H, t, J=7.1Hz), 2.98(3H, s), 4.36(2H, q, J=7.1 Hz), 8.12 (1H, ddd, J=2.2 Hz, 8.1Hz, 10.1 Hz), 8.56(1H, s)

Preparation 7

A mixture of ethyl2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-tert-butoxycarbonyl-2-methylhydrazino)acrylate(2.00 g) and potassium fluoride (0.31 g) in dimethylformamide(5 ml) washeated at 60°˜65° C. for one hour, and refluxed for 5 hours. The mixturewas poured into ice-water (60 ml) to give a solid. The solid wascollected by filtration and dried over phosphorus pentaoxide underreduced pressure to give ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(1.25 g).

Preparation 8

To a mixture of ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.53 g) and allyl hydrogenmalonate (0.35 g) in dichloromethane (10 ml)was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.47 g) and the mixture was stirred at ambient temperature for 18hours. The mixture was poured into a mixture of water (50 ml) anddichloromethane (50 ml). The organic layer was washed with water and,next, brine, dried over magnesium sulfate, concentrated under reducedpressure, and triturated with methanol to give ethyl1-{N-(allyloxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.32 g).

Preparation 9

To a mixture of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (600 g) and 1,3-bis(trimethylsilyl)urea(2.25 g) was stirred at ambient temperature for 15 minutes. To thismixture was added allyl malonyl chloride (3.57 g) and the solution wasstirred at ambient temperature for one hour. The mixture was washed withwater (60 ml), saturated aqueous sodium hydrogencarbonate solution (60ml), and brine (60 ml) in turn, dried over magnesium sulfate, andconcentrated under reduced pressure to give a syrup. The syrup wascrystallized from a mixture of acetone and diisopropyl ether to giveethyl1-{N-(allyloxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(8.01 g).

mp: 124°-126° C. IR(Nujol): 1740, 1730, 1707, 1683 cm⁻¹ NMR(CDCl₃, δ):isomer A 3.36(3H, s), 8.29(1H, s) isomer B 3.48(3H, s), 8.43(1H, s) MS:426(M⁺), 381(M⁺), 369, 353, 338

Preparation 10

To a solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (3.00 g)and diphenylmethylhydrogenmalonate (2.70 g) in dichloromethane (60 ml) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(2.30 g)under ice-cooling. The mixture was stirred at the same condition for 30minutes and at ambient temperature for one hour. The mixture was pouredinto water (60 ml). The organic layer was washed with water (60 ml)andnext brine (60 ml), dried over magnesium sulfate, and concentrated underreduced pressure to give a syrup. The syrup was subjected to a columnchromatography on silicagel (50 g) and eluted with chloroform and amixture of methanol and chloroform (1:99 v/v) to give ethyl1-{N-(diphenylmethyloxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(3.73 g) as a glass.

IR(CHCl₃): 1740, 1697 cm⁻¹ MS: 552(M⁺), 342, 323, 296

Preparation 11

To a solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.00 g)in dichloromethane (10 ml) wasadded 1,3-bis (trimethylsilyl)urea(0.37 g) and the mixture was stirredat ambient temperature for 30 minutes. To the mixture was added ethylmalonyl chloride (0.46 ml) and the solution was stirred at ambienttemperature for 2 hours. Dichloromethane was added to the solution. Thesolution was washed with water (20 ml), saturated aqueous sodiumhydrogencarbonate (20 ml), and brine (20 ml), in turn, dried overmagnesium sulfate, and concentrated under reduced pressure to give aresidue. The residue was crystallized from a mixture of acetone anddiisopropyl ether to give ethyl1-{N-(ethoxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.14 g).

Preparation 12

To a solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro4-oxoquinoline-3-carboxylate (0.50 g) in pyridine (3 ml) was added ethylmalonyl chloride (0.23 ml)) under ice-cooling and the mixture wasstirred at the same temperature for 2 hours. The mixture was poured intoice-water (50 ml) to give a solid. The solid was collected by filtrationand dried over phosphorus pentaoxide under reduced pressure to giveethyl1-{N-(ethoxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.84 g).

mp: 149°-151° C. IR(Nujol): 1740-1730, 1707, 1685 cm⁻¹ NMR(CDCl₃, δ):isomerA 3.82(3H, s), 8.29(1H, s) isomerB 3.48(3H, s), 8.43(1H, s) MS:414(M⁺), 369, 342, 300, 270

Preparation 13

To dioxane (80 ml) solution of 2,3,4,5-tetrafluorobenzoyl chloride(21.25 g) was added dioxane (25 ml) solution of methyl3-dimethylaminoacrylate (12.92 g) with ice-cooling, and triethylamine(14.46 ml) was added thereto with ice-cooling. The mixture was stirredfor 30 minutes at the same temperature, then for 3 hours at roomtemperature, and then for one hour at 50° to 60° C. The mixture wasconcentrated under reduced pressure, then dissolved in methylenechloride (200 ml), washed with water (200 ml) and brine (100 ml) inorder, then dried with sodium sulfate and concentrated under reducedpressure to obtain a syrup product. The syrup product was subjected tocolumn chromatography with silica gel and eluted with a mixed liquid ofmethanol/methylene chloride (3/97, V/V) to obtain methyl3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (15.47 g) as asyrup product.

IR(CHCl₃): 1700-1685, 1625 cm⁻¹ NMR(CDCl₃, δ): 2.89(3H, brs), 3.35(3H,brs), 3.85(3H, s), 7.17-7.31(1H, m), 7.83(1H, s) MS: 305, 273

Preparation 14

To methylene chloride (120 ml) solution of methyl 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (13.2 g) was added methylenechloride (12 ml) solution of 1-tert-butoxycarbonyl-1-methylhydrazine(7.59 g) with ice-cooling, and the mixture was stirred for one hour atthe same temperature and then for 15 hours at room temperature. Thereaction mixture was concentrated under reduced pressure. The residuewas triturated with diisopropyl ether (132 ml). The solid formed wastaken out by filtration and dried with phosphorus pentaoxide underreduced pressure to obtain methyl1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(10.49 g).

mp: 141°-145° C. IR(Nujol): 3400, 1732, 1698 cm⁻¹ NMR(CDCl₃, δ):1.33(3H, s), 1.56(6H, s), 3.43(3H, s), 3.96(3H, s), 8.13(ddd, J=2.2 Hz,8.1 Hz, 10.0 Hz), 8.41(1H, s) Ms: 386(M⁺), 371, 330, 286, 272, 254

Preparation 15

To ethyl acetate solution (55 ml) of 4N hydrochloric acid, was addedmethyl1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(10.85 g) with ice-cooling, and the mixture was stirred for one hour atthe same temperature and then for 14 hours at room temperature. Themixture was concentrated under reduced pressure to obtain a solid. Thesolid was poured into a mixture comprising methylene chloride (150 ml)and water (150 ml). The suspension was neutralized with sodiumhydrogencarbonate. The precipitates were taken out by filtration, washedwith water and dried with phosphorus pentaoxide to obtain a solid. Thesolid was recrystallized from a liquid mixture of methylene chloride anddiisopropyl ether to obtain methyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(4.05 g).

mp: 190°-191° C. IR(Nujol): 3260, 1730 cm⁻¹ NMR(DMSO-d₆, δ): 2.84(3H, d,J=5.7 Hz), 3.77(3H, s), 6.97(1H, q, J=5.7 Hz), 7.97(1H, ddd, J=2.2 Hz,8.31 Hz, 10.5 Hz), 8.65(1H, s) MS: 286, 255, 228, 211

Preparation 16

A suspension of ethyl1-methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(10 g) in water (100 ml) and 37% aqueous formaldehyde (100 ml) washeated to 100° C. for 1 hour. The mixture was cooled and the solidremoved by filtration and washed with water. The resulting yellowcolored solid was dried to constant weight in vacuo over phosphoruspentaoxide to yield ethyl1-[N-(hydroxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(10.25 g).

IR(Nujol ): 3425, 1710, 1620 cm⁻¹ NMR(DMSO-d₆, δ): 1.28(3H, t, J=7 Hz),3.00(3H, s), 4.25(2H, q, J=7Hz), 4.66-4.50(2H, m), 6.30(1H, t, J=6.5Hz), 7.98-7.87(1H, m), 8.95(1H, s)

Preparation 17

A solution of ethyl1-[N-(hydroxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(8.4 g) and triethylamine (3.09 g) in methylene chloride (150 ml) wascooled to 0° C. and treated with acetyl chloride (2.18 g). After 3 hoursthe reaction was diluted with water and shaken in a separating funnel.The organic layer was dried over magnesium sulfate, evaporated, and thecrude product purified by chromatography with silica gel (50% ethylacetate-hexane elution) to yield ethyl1-[N-(ethoxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(2.1 g).

IR(Nujol): 1720, 1610, 1560 cm⁻¹ NMR (CDCl₃ -ppm, δ): 1.26(3H, t, J=7Hz), 1.41(3H, t, J=7.1 Hz), 3.12(3H, s), 3.67-3.43(2H, m), 4.47-4.32(2H,m), 4.54(2H, s), 8.15-8.05(1H, m), 9.05(1H, s) Mass (EI): 358(M⁺)Elemental Analysis for C₁₆ H₁₇ F₃ N₂ O₄ Calcul.: C 53.63 H 4.78 N 7.82Found: C 53.88 H 4.78 N 7.62

Preparation 18

To a solution of ethyl1-(ethoxymethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(200 mg) in dry acetonitrile (2.0 ml) was added trichloromethylsilane(65.8 μl) under ice -cooling and the mixture was stirred for 30 minutes,and then for 10 minutes at room temperature. To the reaction mixture wasadded diisopropyl ether (10 ml), which was then stirred for 15 minutesat ambient temperature. The precipitate was collected by filtration andwashed with diisopropyl ether and dried in vacuo over phosphoruspentaoxide to give ethyl1-(chloromethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(145 mg).

IR(Nujol): 1720, 1600, 1480, 1340 cm⁻¹ Elemental Analysis for C₁₄ H₁₂ClF₃ N₂ O₃ Calcul.: C 48.22 H 3.47 N 8.03 Cl 10.17 Found: C 48.45 H 3.53N 8.01 Cl 9.77

Preparation 19

To a solution of ethyl1-[N-(hydroxymethyl)m-N-ethylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(3.0 g) in dry-dichloromethane(60 ml) was added trichloromethylsilane(1.18 ml) under ice -cooling and the mixture was stirred for 1.5 hoursat the same temperature. To the reaction mixture was added diisopropylether (120 ml), which was then stirred for 2 hours at ambienttemperature. The precipitate was collected by filtration and washed withdiisopropyl ether and n-hexane and dried in vacuo over phosphoruspentaoxide to give ethyl1-[N-(chloromethyl)-N-methylamino]-6,7,8-trifluoro-l,4-dihydro-4-oxoquinoline-3-carboxylate(3.07 g).

IR(Nujol): 1720, 1600, 1480, 1340 cm⁻¹ NMR (CDCl₃, δ): 1.41(3H, t, J=7Hz), 3.20(3H, s), 4.40(2H, q, J=7 Hz), 5.39-5.52(2H, m), 8.02-8.12(1H,m), 9.01(1H, s)

Preparation 20

To dimethylformamide (1.5 ml) solution of diethyl malonate (47.8 μl),was added sodium hydride (24.4 mg) with stirring under ice-cooling, andthe mixture was stirred for 20 minutes with ice-cooling. To the solutionwas added ethyl1-[N-(chloromethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(100 mg) with stirring under ice-cooling, and the mixture was stirredfor 30 minutes at the same temperature. The reaction solution was addedto a mixed solution comprising ethyl acetate (30 ml) and water (30 ml)for extraction. The organic layer was washed with water (30 ml×3) and asaturated brine(30 ml×3), dried over magnesium sulfate and concentratedunder reduced pressure. The residue thus obtained was subjected tocolumn chromatography with silica gel (3 g), eluted with a mixed solventof dichloromethane ethyl acetate (20/1 to 10/1) and concentrated todryness under reduced pressure to obtain ethyl6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(ethoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate(49.1 mg).

IR (Nujol): 1715, 1610, 1560, 1480, 1350 cm-1 NMR (CDCl3, δ):1.16-1.29(6H, m), 1.42(3H, t, J=7 Hz), 3.03(3H, s), 3,47(1H, t, J=7 Hz),3.60-3.74(2H, m), 4.05-4.30 (4H, m), 4.41(2H, q, J=7 Hz), 8.04-8.14(1H,m), 8.62(1H, s)

Preparation 21

In a similar manner as in Preparation 20, the following compound wasobtained.

Ethyl 6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate

IR(Nujol): 1715, 1610, 1560, 1480, 1350, 1220 cm⁻¹ NMR (CDCl₃, δ):1.38(9H, s), 1.42(3H, t, J=7 Hz), 1.45(9H, s), 3.01(3H, s), 3.25(1H, t,J=7 Hz), 3.51-3.65(2H, m), 4.42(2H, q, J=7 Hz), 8.05-8.15(1H, m)8.63(1H, s)

Example 1

To dimethylsulfoxide (2.0 ml) solution of ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(105 mg) and tert-butyl 2-tert-butoxycarbonylacrylate (87.8 mg), wasadded solid potassium tert-butoxide (43.2 mg), and the mixture wasstirred for 6 hours and then for 30 minutes at room temperature. Next,this was heated at 90° C., for 2 hours, then cooled and allowed to standat room temperature overnight. This was diluted with ethyl acetate,washed once with 1N hydrochloric acid and four times each with water,dried over magnesium sulfate and concentrated under reduced pressure toobtain an orange syrup product (134.8 mg). The syrup product wassubjected to column chromatography with silica gel and eluted with amixed solvent of methylene chloride, ethyl acetate (10/1) to obtainethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i,j]cinnoline-3,3-bis(tert-butoxycarbonyl)-8-carboxylate(36.6 mg) as a pale yellow syrup product.

NMR(CDCl3, δ): 1.37(3H, t, J=7 Hz), 1.48(18H, s), 2.78(3H, s), 4.08(2H,s,) 4.39(2H, q, J=7 Hz), 8.29(1H, dd, J=8 and 10 Hz), 8.55(1H, s)MS(EI)M/Z: 508(M+), 452(MH+--But), 408(MH+--CO2But), 509(MH+)

Example 2

Trifluoroacetic acid (1.0 ml) was added to methylene chloride (1.0 ml)solution of ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i,j]-cinnoline-3,3-bis(tert-butoxycarbonyl)-8-carboxylate (36.5 mg), withice-cooling, and this was stirred for 15 minutes at 5° C. or lower andthen allowed to stand at room temperature for 24 hours. The solvent ofthe reaction mixture was removed by distillation, and aqueous sodiumhydrogencarbonate solution was added to the residue, which was thenextracted with methylene chloride (2×5 ml). The basic layer wasacidified with 1M hydrochloric acid, which was then extracted withmethylene chloride (4×5 ml). These extracts were combined and dried overmagnesium sulfate. Then, the solvent was removed therefrom under reducedpressure, and the residue was dried to solid to obtain ethyl4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-3-carboxy-8-carboxylate (7.40 mg) as a white solid. Theaqueous layer was extracted twice each with ethyl acetate and dried overmagnesium sulfate, and the solvent was removed by distillation to obtainethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-3 -carboxy-8-carboxylate (6.10 mg).

NMR(DMSO-d6, δ): 1.28(3H, t, J=7.1 Hz), 2.82(3H, s), 3.84-3.70(2H, m),4.22(2H, q, J=7.1 Hz), 4.30(1H, t, J=5.6 Hz), 8.07(1H, dd, J=8.6 and10.6 Hz), 8.53(1H, s)

Example 3

Dimethylsulfoxide (0.5 ml) solution of ethyl4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-3-carboxy-8-carboxylate(7.4 mg) was heated at 170° C., in annitrogen atmosphere for 30 minutes, then cooled, diluted with ethylacetate, washed with water (4 times), dried over magnesium sulfate andfiltered, and the solvent was removed by distillation under reducedpressure to obtain ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (7.4 mg) as a white solid.

NMR(CDCl3, δ): 141(3H, t, J=7 Hz), 2.87(3H, s), 3.06(2H, t, J=6 Hz),3.50(2H, t, J=6 Hz), 4.39(2H, q, J=7 Hz), 8.15(1H, dd, J=8.6 and 8.6Hz), 8.58(1H, s)

Example 4

Solid potassium tert-butoxide (823 mg) was added to tetrahydrofuran (40ml) solution of ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(2.0 g) and tert-butyl 2-tert-butoxycarbonylacrylate (1.67 g), withstirring and suspending under ice-cooling, and the suspension wasstirred for 0.5 hour with ice-cooling and then 1.5 hours at roomtemperature. The reaction solution was poured into a mixed liquid ofethyl acetate ice-water (150 ml/150 ml) and was adjusted to have pH of3.0 with 1N hydrochloric acid. The organic layer was separated out,washed with water and saline solution, and dried over magnesium sulfate.This was concentrated under reduced pressure to obtain an amorphousproduct. The amorphous product was subjected to column chromatographywith silica gel and eluted with a mixed solvent of methylene chlorideethyl acetate (20/1 to 10/1). The fractions containing the objectproduct were collected, and the solvent was removed by distillationunder reduced pressure. The residue was tritulated with n-hexane, andthe precipitates were filtered out to obtain ethyl 6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.35 g) as an almost whitepowder.

The filtrate was evaporated and dried to solid to also obtain the samecompound ethyl6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate(330 mg).

NMR(CDCl3, δ): 1.38(9H, s), 1.45(9H, s), 1.49(3H, t, J=7 Hz), 3.01(3H,s), 3.25 (1H, t, J=7 Hz), 3.51-3.70(2H, m), 4.41(2H, q, J=7 Hz),8.05-8.15(1H, m), 8.64(1H, s)

Example 5

Methylene chloride (10 ml) solution of ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(1.0 g) and tert-butyl 2-tert-butoxycarbonylacrylate (1.52 g) was cooledin an ice bath in nitrogen atmosphere, and titanium tetrachloride (632.4mg) was dropwise added thereto. After 30 minutes, this was diluted withethyl acetate (100 ml) and then with water (100 ml). The organic layerwas separated out, washed with water (2×50 ml), dried over magnesiumsulfate and concentrated under reduced pressure to obtain an yellowsyrup product. The syrup product was subjected to column chromatographywith silica gel and eluted with a mixed solvent of methylenechloride/ethyl acetate (10/1) to obtain ethyl6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate(988 mg), as a white solid.

Example 6

N-methylpyridone (10 ml) solution of ethyl6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate(500 mg) was stirred at room temperature, and potassium tert-butoxide(117 mg) was added thereto. The solution was stirred for 15 minutes atroom temperature and then for 3.5 hours at 55 to 58° C., and thereafterit was poured into a mixed liquid of ethyl acetate (100 ml) andice-water (100 ml) and was then adjusted to have pH of 5 with 1Nhydrochloric acid. The organic layer separated was combined with anextract obtained by extracting the aqueous layer with ethyl acetate andthen washed with water (3×100 ml) and with saline solution. This wasdried over magnesium sulfate, and the solvent was removed bydistillation. The residue was triturated with diisopropyl ether, and theprecipitates were taken out by filtration and washed with a small amountof diisopropyl ether and then with n-hexane to obtain ethyl4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j}cinnoline-3,3-bis(tert-butoxycarbonyl)-8-carboxylate as a pale yellowpowder.

Example 7

Methylene chloride solution (0.667 ml) of 1M titanium tetrachloride wasgradually added to a solution of methylene chloride (2 ml) andtetrahydrofuran (54.3 μ) containing ethyl6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate(200 mg), with stirring under ice-cooling, and then tert-butyl2-tert-butoxycarbonylacrylate (0.228 g) was added thereto and stirredfor 10 minutes with ice-cooling and then for 15 hours at roomtemperature. The mixture was poured into a mixture of ethyl acetate (20ml) and water (20 ml). The organic layer separated was washed with brineand dried over magnesium sulfate, and the solvent was removed bydistillation under reduced pressure. The residue was then trituratedwith n-hexane. The precipitates were taken out by filtration and driedwith air to obtain ethyl6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate(775.8 mg) as a pale yellow powder.

Example 8

A solution of ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i, j]cinnoline-3,3-bis(tert-butoxycarbonyl)-8-carboxylate(100 mg) in glacial acetic acid (1 ml) was treated with 6M-hydrochloneacid (1 ml) and the solution warmed to reflux for 4 hours. Aftercooling, ethyl acetate was added and the solution washed with water 4times, dried over magnesium sulfate, filtered, evaporated under reducedpressure and dried under high vacuum to yield4,5-difluoro-2,3-dihydro-1-methyl-7-oxo -1H, 7H-pyrido[3,2,1-i,j]cinnoline-3,3-carboxy-8-carboxylic acid (49.5 mg).

NMR(DMSO-d6, δ): 2.89(3H, s), 4.03(2H, d, J=7 Hz), 4.40(1H, t, J=6 Hz),8.31(1H, dd, J=8.5 Hz), 8.83(1H, s), 13.60-13.00(1H, bs), 14.66(1H, bs)

Example 9

A solution of 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-3-carboxy-8-carboxylic acid (42 mg) indimethyl sulfoxide (2 ml) was placed on a preheated oil bath at 150° C.for 20 minutes, then cooled to room temperature. Ethyl acetate (50 ml)was added and the solution washed with water (4×25 ml), dried overmagnesium sulfate, filtered, evaporated under reduced pressure and driedunder high vacuum to yield 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylic acid (25 mg) as a whitesolid.

NMR(DMSO-d6, δ): 2.89(3H, s), 3.14(2H, t, J=6Hz), 3.54(2H, t, J=6 Hz),8.17(1H, dd, J=8.6 and 10.5 Hz), 8.94(1H, s), 14.79(1H, bs)

Example 10

Ethyl1-methylamino-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(9.5 g) and di-tert-butyl methylidenemalonate (13.7 g) were dissolved inmethylene chloride (90 ml). Titanium tetrachloride (3.3 ml) was dropwiseadded thereto with ice-cooling over a period of 40 minutes, and themixture was then stirred for one hour. The reaction solution was pouredinto ice-water, the organic layer was separated and dried over magnesiumsulfate, and the solvent was removed by distillation. The oily productobtained was subjected to silica gel column chromatography (eluentsolvent: ethyl acetate/methylene chloride of 1/20 v/v) to obtain ethyl1-[N-{2,2-bis(tert-butoxycarbonyl)ethyl}-N-methyl]amino-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(8.6 g).

mp: 118°-122° C. NMR(CDCl3, δ): 1.39(12H, s), 1.46(9H, s), 3.00(3H, s),3.19-3.23(1H, m), 3.48-3.62(2H, m), 4.40(2H, q, J=1 Hz), 8.52(1H, s)

Example 11

Ethyl1-[N-{2,2-bis(tert-butoxycarbonyl)ethyl}-N-methyl]amino-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(10.0 g) was dissolved in dimethylsulfoxide (150 ml) and stirred at roomtemperature. Cesium carbonate (3.0 g) was added thereto and the mixturewas stirred for 3 hours at 80° C. After left to be cooled, the reactionsolution was poured into a mixture comprising 5% aqueous citric acidsolution (500 ml) and ethyl acetate (500 ml), the organic layer wasseparated and dried over magnesium sulfate, and the solvent was removedby distillation. The residue was dissolved in ether, and the insolublesubstances were removed by filtration. The filtrate was distilled, andthe residue was subjected to silica gel chromatography (eluent solvent:chloroform) to obtain ethyl3,3-bis(tert-butoxycarbonyl)-4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i,]cinnoline-8-carboxylate (1.6 g).

mp: 169°-173° C. NMR(CDCl3, δ): 1.40(3H, t, J=7.1 Hz), 1.49(18H, s),2.76(3H, s), 4.04(2H, s), 4.39(2H, q, J=7.1 Hz), 8.47(1H, s)

Example 12

Ethyl3,3-bis(tert-butoxycarbonyl)-4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (1.0 g) was dissolved intrifluoroacetic acid (2 ml) and heated at 60° C. for 2 hours. Thereaction solution was poured into isopropyl ether (50 ml), and thecrystals thus precipitated were taken out by filtration to obtain4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-8-ethoxycarbonyl-1H,7H-pyrido[3,2,1-i, j]cinnoline-3-carboxylic acid (0.67 g).

mp: 219°-223° C. (dec) NMR(DMSO-d6, δ): 1.28(3H, t, J=7.1 Hz), 2.78(3H,s), 3.73-3.76(2H, m), 4.18-4.25(3H, m), 8.45(1H, s)

Example 13

4,5,6-Trifluoro-2,3-dihydro-1-methyl-7-oxo-8-ethoxycarbonyl-1H, 7H-pyrido[3,2,1-i, j]cinnoline-3-carboxylic acid (300 mg) was dissolved inN-methylpyrrolidone (6 ml) and heated at 160° C. for 3 hours. After thereaction solution was left to be cooled, water was added thereto, andthis was extracted three times each with chloroform. The organic layerwas dried over magnesium sulfate, and the solvent was removed bydistillation. The residue was subjected to silica gel chromatography(eluent solvent: chloroform) to obtain ethyl 4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (128mg). mp: 236°-240° C. NMR(CDCl3, δ): 1.40(3H, t, J=7.1 Hz), 2.83(3H, s),3.00-3.08, 3.44-3.51 (each 2H, each m), 4.38(2H, q, J=7.1 Hz), 8.49(1H,s)

Example 14

Ethyl 4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylate (30 mg) was added to a mixture of acetic acid(0.4 ml) and 12N hydrochloric acid (0.1 ml) and heated at 100° C. for 2hours. After the reaction solution was left to be cooled, water wasadded thereto, and the crystals as precipitated were taken out byfiltration. These were washed with water, ethanol and ether to obtain4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylic acid (22 mg).

mp: 255°-260° C. (dec.) NMR(DMSO-d6, δ): 2.85(3H, s), 3.10-3.07,3.55-3.49(each 2H, each m), 8.78(1H, s)

Example 15

Ethyl 4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoine-8-carboxylate (62 mg) and benzylamine (50 mg) were added totoluene (2 ml) and heated at 80° C. for 24 hours. The reaction solutionwas dissolved in chloroform, washed with 5% citric acid aqueous solutionand dried over magnesium sulfate, and the solvent was removed bydistillation. The crystals obtained were dispersed in ether and takenout by filtration to obtain ethyl 4,5-difluoro-6-benzylamino-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (59mg).

mp: 186°-190° C. NMR(CDCl3, δ): 1.38(3H, t, J=7.3 Hz), 2.78(3H, s),2.90-2.83, 3.33-3.39(each 2H, each m), 4.36(2H, q, J=7.3 Hz), 4.68,4.70(each 1H, each d, each J=3.9 Hz), 7.22-7.38(5H, m), 8.40(1H, s),10.81 (1H, brs)

Example 16

Ethyl 4,5-difluoro-6-benzylamino-2, 3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (59 mg) was dissolved in amixture of ethanol (10 ml) and acetic acid (10 ml), and 10%palladium-carbon (5 mg) was added thereto and stirred for 24 hours inhydrogen atmosphere. The catalyst was removed by filtration, and thefiltrate was subjected to distillation. The residue was dissolved inchloroform, washed with saturated sodium hydrogencarbonate aqueoussolution and dried over magnesium sulfate, and then the solvent wasremoved by distillation. The crystals thus precipitated out weredispersed in ether and taken out by filtration to obtain ethyl4,5-difluoro-6-amino-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylate (27 mg).

mp: 255°-257° C. NMR(CDCl3, δ): 1.39(3H, t, J=7.1 Hz), 2.80(3H, s),2.89, 3.39(ezch 2H, each t, each J=6.0 Hz), 4.38(2H, q, J=7.1 Hz),7.03(2H, brs), 8.44(1H, s)

Example 17

Ethyl 4,5-difluoro-6-amino-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (20 mg) was added to amixture of acetic acid (0.4 ml) and 12N hydrochloric acid (0.1 ml) andheated at 100° C. for 2 hours. After the reaction solution was left tobe cooled, water was added thereto and the crystals as precipitated weretaken out by filtration. These were washed with water, ethanol and etherin order to obtain4,5-difluoro-6-amino-2,3-dihydro-1-methyl-7-oxo-1H,-pyrido [3,2,1-i,j]cinnoline-8-carboxylic acid (13 mg).

mp: >290° C. NMR(DMSO-d6, δ): 2.80(3H, s), 2.86-2.91, 3.40-3.45(each 2H,each m), 7.71(2H, brs), 8.61(1H, s)

Example 18

A suspension of ethyl1-{N-(allyloxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(1.00 g), cuprous iodide (0.10 g) and potassium tert-butoxide (0.56 g)in dimethyl sulfoxide (5 ml) was stirred at 100°-105° C. for 1.5 hoursin nitrogen. Glacial acetic acid (0.16 ml) was added to the reactionmixture. After cooling, acetone (15 ml) was added to the reactionmixture to give a solid. The solid was collected by filtration, washedwith water, and dried over phosphorus pentaoxide under reduced pressureto give 3-allyl 8-ethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-3,8-dicarboxylate(0.83 g).

Example 19

To a stirred solution of palladium acetate (11 mg) andtriphenylphosphine (26 mg) in a mixture of dimethylformamide (2 ml) andtetrahydrofuran (10 ml) was added a mixture of formic acid (0.09 ml) andtriethylamine (0.41 ml) in tetrahydrofuran (1 ml)at ambient temperaturein nitrogen atmosphere. To the mixture was added 3-allyl 8-ethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline -3,8-dicarboxylate(0.41 g) and the mixture was stirred atambient temperature for 4 hours to give a solid. The solid was collectedby filtration and dried over phosphorus pentaoxide under reducedpressure to give ethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate(148 mg).

Example 20

A suspension of ethyl1-{N-(diphenylmethyloxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(3.68 g), cuprous iodide (0.25 g) and potassium tert-butoxide (1.60 g)in dimethyl sulfoxide (18.4 ml) was stirred at 50°-55° C. for 30 minutesin nitrogen atmosphere and at 100°-105° C. for 1.5 hours. Glacial aceticacid (0.5 ml) was added to the mixture . The mixture was poured intowater (185 ml) to give a solid. The solid was collected by filtration,washed with acetone, and dried over phosphorus pentaoxide under reducedpressure to give 3-diphenylmethyl 8-ethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-3,8-dicarboxylate(1.87 g).

mp: >260° C. IR(Nujol): 1729, 1676 cm⁻¹ NMR(DMSO-d₆, δ): 1.27(3H, t,J=7.1 Hz), 3.34(3H, s), 4.20(2H, q, J=7.1 Hz), 6.79 (1H, s),7.1-7.6(11H, m), 8.52(1H, s) MS: 393, 291, 282, 236, 220, 184, 167

Example 21

To a solution of 3-diphenylmethyl 8-ethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-3,8-dicarboxylate(1.51 g) in a mixture of anisole (1.5 ml)and trifluoroacetic acid (30 ml) was stirred at ambient temperature forone hour,. The mixture was concentrated under reduced pressure to give aresidue. The residue was subjected to a column chromatography on silicagel (30 g) and eluted with a mixture of methanol and dichloromethane(1:99 and then 2:98 v/v) to give ethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylate(0.62 g).

mp: 245° C. (dec.) IR(Nujol): 1727, 1685 cm⁻¹ NMR(DMSO-d₆, δ): 1.30(3H,t, J=7.1 Hz), 3.68(3H, s), 4.06(2H, s), 4.26(2H, q, J=7.1 Hz), 7.98(1H,dd, J=8.5 Hz, 10.5 Hz), 8.84(1H, s) MS: 322(M⁺), 277, 250, 220

Example 22

A suspension of ethyl1-{N-(ethoxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(1.00 g), cuprous iodide (0.10 g), and potassium tert-butoside (0.57 g)in dimethyl sulfoxide (5 ml) was stirred at 100°-105° C. for 1.5 hoursin nitrogen atmosphere. After cooling, acetone (15 ml) was added to thereaction mixture to give a solid. The solid was collected by filtration,washed with water, and dried over phosphorus pentaoxide under reducedpressure to give diethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H,7H-pyrido [3,2,1-i, j]cinnoline-3,8-dicarboxylate (0.87 g).

mp: >260° C. IR(Nujol): 1675 cm⁻¹ NMR(CDCl₃, δ): 7.14(1H, dd, J=7.7 Hz,10.5 Hz), 8.48(1H, s) MS: 394(M⁺), 349(M⁺ -45), 345, 322, 307

Example 23

A suspension of ethyl1-{N-(ethoxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.10 g) and potassium fluoride (0.056 g) in dimethylformamide (0.5 ml)was stirred at 100°-105° C. for 5 hours in nitrogen atmosphere. Aftercooling, water (5 ml) was added to the reaction mixture to give a solid.The solid was collected by filtration, washed with acetone, and driedover phosphorus pentaoxide under reduced pressure to give diethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, -pyrido[3,2,1-i,j]cinnoline-3,8-dicarboxylate(52 mg).

Example 24

A suspension of ethyl1-{N-(ethoxycarbonyl)acetyl-N-methylamino}-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.20 g), cuprous iodide (0.02 g), and sodium hydride (60% in oilsuspension, 0.04 g) in dimethylformamide (1 ml)was stirred at 100°-105°C. for 4 hours in nitrogen atmosphere. After cooling, water (10 ml) wasadded to the mixture to give a solid. The solid was collected byfiltration, washed with water, and dried over phosphorus pentaoxideunder reduced pressure to give diethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido [3,2,1-i,j]cinnoline-3,8-dicarboxylate(0.16 g).

Example 25

A solution of diethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo -1H,7H-pyrido[3,2,1-i, j]cinnoline-3,8-dicarboxylate(100 mg) in a mixture ofwater (0.05 ml) and trifluoroacetic acid (1.0 ml) was heated underreflux for 3 hours. The mixture was purified by preparative thin layerchromatography (development with ethyl acetate) to give ethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,21i,j]cinnoline -8-carboxylate(36 mg).

Example 26

To a suspension of ethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate(200 mg) in tetrahydrofuran(2 ml) was added borane-methyl sulfide complex (0.1 ml) underice-cooling and the mixture was stirred at ambient temperature for 6days. Methanol (0.5 ml) was added to the reaction mixture underice-cooling and the mixture was stirred at ambient temperature for onehour. The mixture was concentrated under reduced pressure and purifiedby preparative thin layer chromatography (development with ethylacetate) to give ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate(5.3 mg).

Example 27

To a suspension of diethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-3,8-dicarboxylate(510 mg) in a mixture of concentratedhydrochloric acid (0.61 ml) and glacial acetic acid (3.06 ml) was heatedat 100°-105° C. for 5 hours. After cooling, water (15.3 ml) was added tothe mixture. The resulted solid was collected by filtration and driedover phosphorus pentaoxide under reduced pressure to give4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylic acid (287 mg).

Example 28

Pyridine (2 ml) suspension containing ethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylate (300 mg) and sodium boron hydride (100 mg) wasrefluxed for 8 hours in nitrogen atmosphere. The solid was separated byfiltration, and the filtrate was concentrated under reduced pressure toobtain a syrup product. The syrup product was purified by a previouslyprepared thin layer chromatography (using ethyl acetate as a developer),to obtain ethyl 4,5-difluoro-2,3,7,8-tetrahydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i. j]cinnoline-8-carboxylate (36.7 mg) having Rf valueof 0.82 and ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline -8-carboxylate (5.6 mg) having Rf valueof 0.48.

Physical properties of ethyl4,5-difluoro-2,3,7,8-tetrahydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i.j]cinnoline-8-carboxylate were as follows:

mp: 82°-84° C. IR(Nujol): 1658, 1630 cm⁻¹ MS: 310, 295, 237

Example 29

Sodium boron hydride (46 mg) was added to a mixture solution of borontrifluoride-diethyl ether complex (0.15 ml) and tetrahydrofurancontaining ethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H,7H-pyrido [3,2,1-i., j]cinnoline-8-carboxylate (100 mg), withice-cooling, and the mixture was stirred for one hour at roomtemperature. The solid was removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain a syrup product. The syrupproduct was purified by a previously prepared thin layer chromatography(using ethyl acetate as a developer), to obtain ethyl4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i.j]cinnoline-8-carboxylate (7.9 mg) and ethyl4,5-difluoro-2,3,7,8-tetrahydro-1-methyl-7-oxo-1H, -pyrido[3,2,1-i,j]cinnoline-8-carboxylate (3.5 mg).

Example 30

Active manganese dioxide (30 mg) was added to ethyl acetate (1 ml)solution of ethyl 4,5-difluoro-2,3,7,8-tetrahydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (20 mg), and the mixturewas stirred for 2 days at room temperature. The solid was removed byfiltration, and the filtrate was concentrated under reduced pressure toobtain a syrup product. The syrup product was purified by a previouslyprepared thin layer chromatography (using ethyl acetate as a developer),to obtain ethyl 4,5-difluoro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylate (11.2 mg).

Example 31

To dioxane (1 ml) suspension of sodium boron hydride (60 ml), was addeddioxane (0.2 ml) solution of trifluoroacetic acid (181 mg) at 10° C. orlower. To the mixture, was added ethyl4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylate (100 mg). The mixture was heated at 100° to105° C. for 5 hours. After cooled, the solid was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain asyrup product. The syrup product was purified by a previously preparedthin layer chromatography (using ethyl acetate as a developer), toobtain ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate (9.4 mg).

Example 32

Ethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylate (100 mg) was added to phosphoryl chloride(0.35 ml) at room temperature. The mixture was stirred for 1.5 hours,and the excess phosphoryl chloride was removed at 20° C. (20 mmHg). Theoily product thus formed was left under high vacuum for 30 minutes toremove the remaining phosphoryl chloride, and the residue was dissolvedin ethylene glycol dimethyl ether (5 ml). The solution was cooled in anice bath, and sodium boron hydride was added thereto with vigorouslystirring. The mixture was stirred for one hour at room temperature, and1N hydrochloric acid (1 ml) was dropwise added thereto. The solvent wasremoved by distillation, and water (3 ml) was added to the residue. Theprecipitates formed were taken out by filtration and dissolved in ethylacetate, and the solution was purified by a previously prepared thinlayer chromatography (using ethyl acetate as a developer) to obtainethyl 4,5-difluoro-2,3-dihydro-1 -methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylic acid (10.0 mg).

Example 33

A solution of ethyl 4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylate(152 mg) in a mixture ofconcentrated hydrochloric acid (0.2 ml) and glacial acetic acid (1 ml)was refluxed for 5 hours. After cooling, water (5 ml) was added to themixture. A obtained solid was collected by filtration and dried overphosphorus pentaoxide under reduced pressure to give4,5-difluoro-2,3-dihydro-1-methyl-2,7-dioxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylic acid(111 mg).

mp: >260° C. IR(Nujol): 1735, 1675 cm⁻¹ NMR(DMSO-d₆, δ): 3.77(3H, s),4.16(2H, s), 8.23(1H, dd, J=8.3 Hz, 10.1 Hz, 10.1 Hz), 9.06 (1H, s) MS:294(M⁺), 250, 221

Example 34

Dimethylformamide (7.5 ml) solution of diethyl malonate (239 μl) wasadded to sodium hydride (122 mg) with stirring under ice-cooling and wasstirred for 20 minutes with ice-cooling. To the solution was added ethyl1-[N-(chloromethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(500 mg), and the mixture was stirred for one hour with ice-cooling.This was then heated up to 50° C. and stirred for 3 hours to effectring-closing reaction. The reaction solution was added to a mixturesolution comprising ethyl acetate (150 ml) and water (150 ml) forextraction. The organic layer was washed with water (150 ml×3) and withsaturated brine(100 ml×1), dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel (15 g) column chromatography, eluted with amixed solvent comprising dichloromethane and ethyl acetate (20/1 to10/1) and concentrated to dryness under reduced pressure to obtain ethyl4,5-difluoro-2,3,-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-3,3-bis(ethoxycarbonyl)-8-carboxylate (183 mg).

IR(Nujol): 1730, 1610, 1560 cm⁻¹ NMR (CDCl₃, δ): 1.30(6H, t, J=7 Hz),1.40(3H, t, J=7 Hz), 2.77(3H, s), 4.14(2H, s), 4.20-4.45(6H, m),8.28-8.37(1H, m), 8.55(1H, s)

Example 35

In a similar manner as in Example 34, the following compound wasobtained.

Ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H, -pyrido[3,2,1-i,j]cinnoline-3,3-bis(tert-butoxycarbonyl)-8-carboxylate NMR (CDCl₃, δ):1.37(3H , t, J=7 Hz), 1.48(18 H, s), 2.78(3H, s), 4.07(2H, s), 4.39(2H,q, J=7 Hz), 8.25-8.34(1H, m), 8.54(1H, s)

Referential Example 1

4,5-difluoro-6-amino-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido[3,2,1-i,j]cinnoline-8-carboxylic acid (4 mg) and pyrrolidine (10 μl) were addedto acetonitrile (1 ml) and heated at 80° C. for 3 hours, and the solventwas removed by distillation. The residue was washed with ethanol andether in order to obtain5-fluoro-4-(pyrrolidin-1-yl)-6-amino-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-i, j]cinnoline-8-carboxylic acid (2 mg).

mp: >290° C. NMR(CDCl3, δ): 1.97-2.06(4H, m), 2.79-2.85(2H, m), 2.86(3H,s), 3.30-3.35 (2H, m), 3.44-3.53(4H, m), 6.57(2H, brs), 8.66(1H, s)

We claim:
 1. A compound of the formula: ##STR7## wherein R¹ is ahydrogen atom or a carboxyl-protecting group;R² is a hydrogen atom or alower alkyl group; X¹ is a hydrogen atom or a halogen atom; X² is ahalogen atom; X_(a) ⁵ is a hydrogen atom or a halogen atom; A is amethylene group; a group of >CH--COOR⁴, or a group of: ##STR8## in whichR⁴, R⁵ and R⁶ each are a hydrogen atom or a carboxyl-protecting group; Bis a methylene group or a carbonyl group; provided that both A and Bmust not be methylene groups at the same time, or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1, wherein R¹, R⁴, R⁵and R⁶ each are a carboxyl-protecting group.
 3. A compound of claim 2,whereinA is a methylene group; and B is a carbonyl group, A is a groupof >CH--COOR⁴ ; wherein R⁴ is a hydrogen atom or a carboxyl-protectinggroup, and B is a methylene group or a carbonyl group, or A is a groupof: ##STR9## wherein R⁵ and R⁶ are each as defined above; and B is amethylene group.
 4. A compound of claim 2, whereinR¹ is a hydrogen atomor a lower alkyl group; R² is a lower alkyl group; X¹ is a halogen atom;R⁴, R⁵ and R⁶ each are a hydrogen atom or a lower alkyl group.